The Hospital for Sick Children, Toronto, Ontario, Canada.
Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
Nat Commun. 2024 Nov 4;15(1):9517. doi: 10.1038/s41467-024-53689-1.
White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical 'atrophy' identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical 'atrophy' showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.
脑白质高信号指数反映了脑白质的结构异常，包括轴突损伤。后者可能会导致大脑皮层萎缩，这是痴呆症的一个关键特征。在这里，我们报告了一项对来自 10 个队列的 51065 个人的研究，结果表明脑白质高信号体积越高，皮质厚度越低。对脑白质高信号相关的“萎缩”的meta-GWAS 确定了 20 个全基因组显著位点，并且富集了血管细胞类型、星形胶质细胞和少突胶质细胞特异性的基因。脑白质高信号相关的皮质“萎缩”与血管风险特征和神经退行性变的血浆生物标志物呈正遗传相关，与认知功能呈负遗传相关。20 个位点中的 15 个调节了大脑皮层中 54 个基因的表达，这些基因及其共表达基因在轴突细胞骨架和细胞内运输的生物学过程中富集。在表达特定于具有长程轴突穿过白质的兴奋性神经元的基因的皮质区域中，脑白质高信号与皮质厚度的关联最为显著。基于 meta-GWAS 的多基因风险评分在 500348 名独立个体的样本中预测了血管性和所有原因的痴呆。因此，脑白质高信号相关皮质萎缩的遗传学涉及血管和神经元过程，并增加了痴呆风险。
